This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent is pyrimidin-2-yl, preferably substituted by halogen at its 5-position; and the other is a 4 carbon alkylene chain bearing a 4-fluorophenyl ring at its terminus. The terminal carbon is also bonded to an oxygen atom giving either a carbonyl, carbinol, or ketal functional group. Additionally, the terminal carbon can bear a substituent such as an alkyl group or a second 4-fluorophenyl ring.
Related art may be viewed in light of the following general structural formula 1 ##STR1## in which Ar is a phenyl ring, X is a carbonyl or carbinol group, alk is an alkylene chain, and B is a heterocycle. In general, the instant compounds may be classified as relatives of antipsychotic butyrophenone compounds and carbinol derivatives. In this regard, the state of the art is reviewed in Chap. 56 of Burger's Medicinal Chemistry, 4th Edition, Part III, M. E. Wolff, Editor, John Wiley & Sons, New York (1981) pages 917-928.
The most closely related art, however, appears to be that contained in a series of three patents issued to Janssen relating to 1-butyl-4-heteroarylpiperazine compounds possessing, among other actions, CNS depressant properties.
In U.S. Pat. No. 2,979,508, issued Apr. 11, 1961, a series of compounds was disclosed in which Ar was substituted phenyl; X was carbonyl or carbinol; alk was C.sub.1 to C.sub.6 alkylene; and B could be--2-pyrimidinyl or 2-pyridinyl. Compounds (1a) and (1b) were specifically disclosed. ##STR2## There is no disclosure of a halogen substituent on the pyrimidinyl ring; and no specific disclosure of a fluorophenylbutanol chain coupled to a pyrimidinylpiperazine moiety.
In U.S. Pat. No. 2,985,657, issued May 23, 1961; a series of butyrophenones was disclosed in which Ar was halophenyl; X was carbonyl, alk was C.sub.1 to C.sub.4 alkylene; and B was pyrimidinyl and chloropyridazinyl among other heterocycles. Specifically disclosed were the following two compounds shown below as (1c) and (1d). ##STR3## Compound (1c) has also been disclosed in German Offen. DE No. 2,053,759, May 27, 1971. Again, no halogenated pyrimidinyl rings were disclosed or claimed.
In U.S. Pat. No. 2,973,360, issued Feb. 28, 1961; a series of CNS depressant compounds is disclosed with Ar being 2-thienyl; X being carbonyl or carbinol; alk being C.sub.2 and C.sub.3 alkylene; and B being 2-pyrimidinyl or 2-pyridyl. The most pertinent compound specifically exemplified and claimed in this patent is shown below as structure (1e). ##STR4##
The following references, while related, are less relevant to the new compounds disclosed in this application.
Regnier, et al., U.S. Pat. No. 3,299,067, issued Jan. 17, 1967 discloses compounds comprising a benzyl-type moiety attached to the 2-pyrimidinylpiperazine. A specific example of this series which is said to be useful as peripheral vasodilators, analgesics and antiinflammatory agents, is shown below as structure (2). ##STR5##
U.S. Pat. No. 3,808,210, issued to Regnier, et al., in April 1974 relates to a series of aryloxypropanolamine antihypertensive compounds having a pyrimidinylpiperazine moiety as in (3). However, these compounds are not butyrophenones or derivatives. ##STR6##
U.S. Pat. No. 4,316,899 issued to Markwell on Feb. 23, 1982 relates to another series of aryloxypropanolamine antihypertensive compounds containing a pyrimidinylpiperazine moiety as exemplified by structure (4). ##STR7##